ClinVar Miner

Submissions for variant NM_000080.4(CHRNE):c.103T>C (p.Tyr35His)

gnomAD frequency: 0.00061  dbSNP: rs144169073
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000413280 SCV000333199 uncertain significance not provided 2015-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000413280 SCV000490469 likely pathogenic not provided 2022-02-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19544078, 21940170, 24295813, 12417530, 29189923, 31980526, 17878953)
Athena Diagnostics Inc RCV000413280 SCV000612745 likely pathogenic not provided 2016-10-13 criteria provided, single submitter clinical testing
Invitae RCV000551170 SCV000641235 pathogenic Congenital myasthenic syndrome 4A 2021-12-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 35 of the CHRNE protein (p.Tyr35His). This variant is present in population databases (rs144169073, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 12417530, 17878953, 21940170, 24295813). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Tyr15His. ClinVar contains an entry for this variant (Variation ID: 282036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRNE protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000825313 SCV000966608 uncertain significance not specified 2018-01-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr35His variant in CHRNE has been reported in the compound heterozygous state in 6 indiv iduals with congenital myasthenic syndrome, and segregated with disease in two a ffected members of one family (reported as p.Tyr15His; Ealing 2002, Palace 2012, Webster 2014). It has also been identified in 0.1% (146/126616) of European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut; dbSNP rs144169073). In vitro functional studies provide some evidence tha t the p.Tyr35His variant may impact protein function (Ealing 2002). However, the se types of assays may not accurately represent biological function. Computation al prediction tools and conservation analysis also suggest that the variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, while there is some suspicion for a pathogenic role , the clinical significance of the p.Tyr35His variant is uncertain due to its fr equency in the general population. ACMG/AMP Criteria applied: PM3_Supporting; PS 4_Moderate; PP3; PS3_Supporting; BS1_Supporting.
Baylor Genetics RCV001004609 SCV001163795 pathogenic Congenital myasthenic syndrome 4C criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001125182 SCV001284221 uncertain significance Congenital myasthenic syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001328993 SCV001520272 pathogenic Congenital myasthenic syndrome 4B 2019-11-26 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Practice for Gait Abnormalities, David Pomarino,Competency Network Toe Walking c/o Practice Pomarino RCV002051834 SCV002318993 likely pathogenic Toe walking 2021-11-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001125182 SCV002547813 likely pathogenic Congenital myasthenic syndrome 2022-05-12 criteria provided, single submitter clinical testing Variant summary: CHRNE c.103T>C (p.Tyr35His) results in a conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251424 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency does not allow conclusions about variant significance. c.103T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with features of Congenital Myasthenic Syndrome (example, Ealing_2002, Denning_2007, Palace_2012, Webster_2014, McMacken_2018, Clair Hou_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=4; Pathogenic/Likely Pathogenic, n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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